Abstract Individuals suffering from chronic neurological disorders, such as spinal cord injury (SCI), are at greater risk of serious life-threatening complications from infections, including Influenza A virus (IAV) and pneumonia. Infections are the leading cause of re-hospitalization and mortality in patients living with chronic SCI. Therefore, reducing complications from infections is critical for improving the health and life span of SCI patients. Several groups, including ours, have endeavored to uncover the mechanisms underlying SCI-induced immune depression. For example, high-thoracic (T3) SCI disrupts sympathetic regulation of lymphoid organs and leads to impaired antibody synthesis and increased splenocyte apoptosis. Elegant studies by Ueno and colleagues demonstrated that high-thoracic SCI-induced immune dysfunction is due, in large part, to massive reorganization of the spinal sympathetic reflex circuit, e.g. the recruitment of glutamatergic interneurons, that results in increased sensitivity of this circuit. Silencing these glutamatergic interneurons restored immune balance, in the absence of pathogen challenge, demonstrating that immune balance can be affected by neurogenic mechanisms. However, the mediator(s) of pathological plasticity and glutamatergic interneuron activation post-SCI have not been established. We have exciting preliminary data suggesting that inhibiting soluble Tumor Necrosis Factor (sTNF) in the spinal cord following SCI: attenuates neuroinflammation and aberrant neuronal plasticity and activation, reduces immune dysfunction, and improves antiviral immunity (reduced viral load, increased specific CD8 T cells). Collectively, these data provide for a strong scientific premise to explore the role of sTNF in SCI- induced immune dysfunction. We hypothesize that heightened levels of sTNF in the spinal cord after injury play a crucial role in triggering robust neuroinflammation (e.g., NF-kB activation) and aberrant plasticity that, in turn, lead to hyperactivity of sympathetic circuitry after SCI and peripheral immune dysfunction. These important findings highlight the role of local sTNF signaling in influencing peripheral immunity. Based upon these data, in the following specific aims, we will: Aim 1: Determine the extent that sTNF/TNFR1 signaling in neurons contributes to immune depression following SCI. Aim 2: Investigate the contribution of sTNF to extrinsic (peripheral) factors of impaired antiviral immune responses in chronic SCI mice.